A HIPPOCAMPAL FEAR ENGRAM MEDIATES MEMORY IMPAIRMENTS AND DESPAIR

Classic PTSD symptoms have been linked to maladaptive fear memory processing, involving fear generalization and impaired extinction learning. In contrast, cognitive and depressive symptoms remain understudied. Here, we investigate the mechanistic link between maladaptive fear, memory impairments and despair.
C57BL/6J mice received bilateral dorsal dentate gyrus (dDG) injections of AAV-Fos::CreERT2 and Cre-dependent DREADD hM4Di or mCherry. After 3-weeks, mice underwent contextual fear conditioning with low (3×0.45 mA) or high (3×0.8 mA) shocks, followed by 4-hydroxytamoxifen (25 mg/kg, i.p.) to label active engram cells. In a subgroup of animals, the tagging was done in a neutral context prior to conditioning. Mice were later tested for fear retrieval, generalization, novel object recognition (NOR), and forced swim test (FST). Clozapine-N-oxide (5 mg/kg, i.p.) was administered 30 min before each test.
High- but not low-intensity-conditioning induced generalization and impaired extinction. Low-intensity did not induce memory deficits and inhibition of the engram had no effect on the NOR or FST. High-intensity-conditioning induced memory impairments that were prevented by inhibition of the engram which also attenuated fear generalization and reduced immobility in the FST. This was accompanied by increased CA1/CA3 activity. The inhibition of a dDG random engram failed to rescue memory deficits and induced an increase in immobility in the FST.
Maladaptive, but not adaptive fear memory, induces generalization, memory impairments and mediates depressive-like behaviours. The inhibition of this engram rescues these effects likely by restoring hippocampal activity.